The inoculum effect and band‐pass bacterial response to periodic antibiotic treatment

Molecular Systems Biology

Cheemeng Tan²  Robert Phillip Smith²  Jaydeep K Srimani²  Katherine A Riccione²  Sameer Prasada²  Meta Kuehn¹ 

[1] Department of Biochemistry, Duke University Medical Center, Durham, NC, USA;Department of Biomedical Engineering, Duke University, Durham, NC, USA

关键词: antibiotic;    bacteria;    bistability;    inoculum effect;   

DOI  :  10.1038/msb.2012.49

来源: Wiley

【 摘 要 】

Abstract

The inoculum effect (IE) refers to the decreasing efficacy of an antibiotic with increasing bacterial density. It represents a unique strategy of antibiotic tolerance and it can complicate design of effective antibiotic treatment of bacterial infections. To gain insight into this phenomenon, we have analyzed responses of a lab strain of Escherichia coli to antibiotics that target the ribosome. We show that the IE can be explained by bistable inhibition of bacterial growth. A critical requirement for this bistability is sufficiently fast degradation of ribosomes, which can result from antibiotic-induced heat-shock response. Furthermore, antibiotics that elicit the IE can lead to ‘band-pass’ response of bacterial growth to periodic antibiotic treatment: the treatment efficacy drastically diminishes at intermediate frequencies of treatment. Our proposed mechanism for the IE may be generally applicable to other bacterial species treated with antibiotics targeting the ribosomes.

Synopsis

The efficacy of many antibiotics decreases with increasing bacterial density, a phenomenon called the ‘inoculum effect’ (IE). This study reveals that, for ribosome-targeting antibiotics, IE is due to bistable inhibition of bacterial growth, which reduces the efficacy of certain treatment frequencies.

• For antibiotics that target the ribosome, the generation of the inoculum effect (IE) can be explained by bistable inhibition of cell growth.
• Using mathematical modeling and experimentation, we demonstrate that a key parameter for this to occur is sufficiently fast degradation of ribosomal components.
• We show that one mechanism that can trigger fast degradation of ribosomal components is when an antibiotic induces the heat-shock response.
• An antibiotic causing IE can cause a drastic time delay in bacterial recovery upon removal of the antibiotics, which leads to a reduction in antibiotic efficacy when antibiotics are applied at intermediate frequencies.

【 授权许可】

CC BY-NC-SA   
Copyright © 2012 EMBO and Macmillan Publishers Limited

Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.